Type 2 diabetes mellitus (T2DM) is a polygenic, heterogeneous disorder with a large inherited component that is characterized by the presence of both beta cell dysfunction and insulin resistance. We have identified a region on chromosome 15q that is linked to insulin levels at 30 minutes on an oral glucose tolerance test in the Old Order Amish. This same region on chromosome 15q has been link to T2DM in Japanese and Mexican Americans. We hypothesize that at least one T2DM susceptibility gene resides on chromosome 15q and it is likely that the gene(s) is involved with beta cell function/insulin secretion. The goal of this grant proposal is to positionally clone the insulin secretion/T2DM susceptibility gene(s) on chromosome 15q in the Old Order Amish population. We believe that this goal can be achieved by 1) further localizing the region to which we have previously detected evidence for linkage to insulin 30 through saturation of this area with more microsatellite markers, 2) screening positional candidate genes for sequence variation in subsets of Amish with T2DM and nondiabetic subjects with extremes of insulin secretion (high and low), and then performing pedigree-based association analyses to detect linkage disequilibrium and 3) linkage disequilibrium mapping using a case control design. The Old Order Amish are an ideal population for this type of study as they are a young founder population and linkage disequilibrium extends over larger intervals than in most outbred populations, thus facilitating our ability to identify associated SNPs and haplotype blocks and in turn the pathogenic mutation(s). By identifying susceptibility genes involved in the development of T2DM, we will provide critical insights into the molecular, cellular, and pathophysiological mechanisms underlying T2DM which in turn will lead to new preventative strategies as well as new molecular targets for the design of novel therapeutic agents. [unreadable] [unreadable]